The pathologic conditions of atherosclerosis and coronary heart disease are secondary to hyperlipidemia and particularly hypercholesterolemia. While the disorder is greatly enhanced by the consumption of high fat diets in the Western world, individuals are also genetically predisposed to the development of the atherogenic conditions which are multifactorial in nature. Regardless of the underlying genetic causes however, transgenic animal studies have demonstrated that enhanced hepatic expression of the LDL receptor and apolipoprotein A1 genes suppressed plasma LDL cholesterol and elevated plasma HDL cholesterol levels in normal animals, respectively. We propose that these desirable biochemical phenotypes in plasma can also be achieved by somatic delivery of the plasma lipid modulating genes into the liver. Our laboratory has recently demonstrated that hepatocytes can be transduced in vivo with recombinant retroviral vectors by direct fusion into the portal vein of partially hepatectomized mice, which resulted in persistent expression of the recombinant genes for at least 6 months in the recipients. In addition, we have obtained preliminary evidence that hepatocytes can be very efficiently transduced in vivo with recombinant adenoviral vectors by interportal vein injection with no apparent hepatic pathology in mice. Furthermore, recombinant genes coupled with ligands for hepato-specific receptors can be introduced into hepatocytes quantitatively by receptor mediated endocytosis. All of these technologies will be further developed and applied in the direct delivery of the LDL receptor gene into the liver of Watanabe hereditary hyperlipidemic rabbits which are genetically predisposed to atherosclerosis due to LDL receptor deficiency. In addition to this and other genetic animal models created by Project 1, the dietary model of atherosclerosis will also be tested. The heterozygous Watanabe rabbits are predisposed to hypercholesterolemia and vascular plaque development when fed a high fat diet. In addition to LDL receptor, other therapeutic genes such as apolipoprotein A-1 and cholesterol-7a-hydroxylase will also be delivered to the liver of these animals maintained on such atherosclerosis-inducing diets. Successful correction of the biochemical and pathologic phenotype in these genetic and dietary animal model systems by direct hepatic gene transfer will form the scientific basis for further gene therapy of atherosclerosis and coronary heart disease in man.